title: A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis.
abstract: Transcription factors are frequently altered in leukaemia through chromosomal translocation, mutation or aberrant expression. AML1-ETO, a fusion protein generated by the t(8;21) translocation in acute myeloid leukaemia, is a transcription factor implicated in both gene repression and activation. AML1-ETO oligomerization, mediated by the NHR2 domain, is critical for leukaemogenesis, making it important to identify co-regulatory factors that 'read' the NHR2 oligomerization and contribute to leukaemogenesis. Here we show that, in human leukaemic cells, AML1-ETO resides in and functions through a stable AML1-ETO-containing transcription factor complex (AETFC) that contains several haematopoietic transcription (co)factors. These AETFC components stabilize the complex through multivalent interactions, provide multiple DNA-binding domains for diverse target genes, co-localize genome wide, cooperatively regulate gene expression, and contribute to leukaemogenesis. Within the AETFC complex, AML1-ETO oligomerization is required for a specific interaction between the oligomerized NHR2 domain and a novel NHR2-binding (N2B) motif in E proteins. Crystallographic analysis of the NHR2-N2B complex reveals a unique interaction pattern in which an N2B peptide makes direct contact with side chains of two NHR2 domains as a dimer, providing a novel model of how dimeric/oligomeric transcription factors create a new protein-binding interface through dimerization/oligomerization. Intriguingly, disruption of this interaction by point mutations abrogates AML1-ETO-induced haematopoietic stem/progenitor cell self-renewal and leukaemogenesis. These results reveal new mechanisms of action of AML1-ETO, and provide a potential therapeutic target in t(8;21)-positive acute myeloid leukaemia.
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Sun
authors.forename: Zhanxin
authors.initials: Z
authors.lastname: Wang
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.forename: Nils
authors.initials: N
authors.lastname: Kost
authors.forename: T David
authors.initials: TD
authors.lastname: Soong
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Chen
authors.forename: Zhanyun
authors.initials: Z
authors.lastname: Tang
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Nakadai
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fischle
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002455:Cell Division; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000737:chemistry / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000378:metabolism*; D017354:Point Mutation; D011485:Protein Binding; D055503:Protein Multimerization; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D046912:Multiprotein Complexes; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors